Parasite maturation and host serum iron influence the labile iron pool of erythrocyte stage<i>Plasmodium falciparum</i>

Clark, Martha A.; Fisher, Nancy C.; Kasthuri, Raj S.; Cerami, Anthony

doi:10.1111/bjh.12234

Cited by 37 publications

(41 citation statements)

References 39 publications

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“…It has been suggested that parasite growth is inhibited during IDA due to an additional reduction in the bioavailability of iron (46). While it remains unclear where and how the parasite obtains the iron necessary for growth, evidence suggests that the parasite meets some of its need by importing iron from serum (16,47,48). Reduced serum iron in individuals with IDA may reduce the parasite's access to iron, thereby inhibiting growth.…”

Section: Discussionmentioning

confidence: 99%

“…In liver-stage infection, reduced iron bioavailability brought on by previously established bloodstage infection inhibits the development of sporozoites, thereby preventing compound infections (15). It has been speculated that an excess of iron bioavailability resulting from iron supplementation may subvert these processes and encourage parasite growth (16,17). Expression of the iron-regulatory protein lipocalin 2 (LCN2) is increased during malaria infection (18), and studies of knockout mice indicate a key role for LCN2 in modulating the innate and adaptive immune responses to infection through its influence on iron recycling (19).…”

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confidence: 99%

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Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

et al. 2015

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The treatment of iron deficiency in areas of high malaria transmission is complicated by evidence which suggests that iron deficiency anemia protects against malaria, while iron supplementation increases malaria risk. Iron deficiency anemia results in an array of pathologies, including reduced systemic iron bioavailability and abnormal erythrocyte physiology; however, the mechanisms by which these pathologies influence malaria infection are not well defined. In the present study, the response to malaria infection was examined in a mutant mouse line, Tfrc MRI24910 , identified during an N-ethyl-N-nitrosourea (ENU) screen. This line carries a missense mutation in the gene for transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with dietary iron deficiency anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Systemic iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic iron deficiency without significantly altering overall iron homeostasis. When infected with the rodent malaria parasite Plasmodium chabaudi adami, mice displayed increased parasitemia and succumbed to infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to dietary iron deficiency anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to malaria in mice. These findings may have implications for the management of iron deficiency in the context of malaria. Iron deficiency and supplementation can influence the risk and outcome of malaria infection. Epidemiology studies have indicated that iron deficiency anemia (IDA) is associated with a reduced risk of malaria in children and pregnant women (1-5), whereas clinical trials have demonstrated that iron supplementation in the absence of adequate health care increases the risk of malaria (6, 7). While the mechanisms underlying these outcomes are not well defined, it is clear that two major factors contribute: iron bioavailability and erythrocyte physiology.Iron bioavailability and homeostasis in the host during malaria infection are complex and incompletely understood (8). During infection, expression of the iron-regulatory hormone hepcidin increases significantly, leading to reduced dietary iron absorption and increased iron storage (9-12). The restriction of iron bioavailability may be a host defense mechanism designed to inhibit parasite access to iron, although the source of iron utilized by the parasite is still unclear (13,14). In liver-stage infection, reduced iron bioavailability brought on by previously ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

et al. 2015

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“…Recent work confirmed that infected RBCs contain a larger labile iron pool than uninfected RBCs and showed that this pool increases during asexual development [19]. Surprisingly, the source of the parasite iron is still unclear.…”

Section: The Art Activator: What Is It and Where Does It Come From?mentioning

confidence: 97%

Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins

Klonis

Creek

Tilley

2013

Current Opinion in Microbiology

104

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“…citrate, albumin). Because iron binds to these ligands with less affinity than to transferrin, NTBI may be more available to circulating parasites than transferrin‐bound iron (Clark et al , 2013). This line of evidence would suggest that women in the second half of pregnancy are at increased risk compared to their pre‐pregnancy state or in the first half of pregnancy, because iron absorption and thus, the possible production of NTBI due to iron supplementation may be more pronounced in individuals with iron deficiency than in those who are iron replete (Brittenham et al , 2014).…”

Section: Safety Of Antenatal Iron Interventions In Malaria‐endemic Sementioning

confidence: 99%

Safety and benefits of antenatal oral iron supplementation in low‐income countries: a review

2017

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SummaryThe World Health Organization recommends universal iron supplementation of 30–60 mg/day in pregnancy but coverage is low in most countries. Its efficacy is uncertain, however, and there has been a vigorous debate in the last decade about its safety, particularly in areas with a high burden of malaria and other infectious diseases. We reviewed the evidence on the safety and efficacy of antenatal iron supplementation in low‐income countries. We found no evidence that daily supplementation at a dose of 60 mg leads to increased maternal Plasmodium infection risk. On the other hand, recent meta‐analyses found that antenatal iron supplementation provides benefits for maternal health (severe anaemia at postpartum, blood transfusion). For neonates, there was a reduced prematurity risk, and only a small or no effect on birth weight. A recent trial showed, however, that benefits of antenatal iron supplementation on maternal and neonatal health vary by maternal iron status, with substantial benefits in iron‐deficient women. The benefits of universal iron supplementation are likely to vary with the prevalence of iron deficiency. As a consequence, the balance between benefits and risks is probably more favourable in low‐income countries than in high‐income countries despite the higher exposure to infectious pathogens.

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Parasite maturation and host serum iron influence the labile iron pool of erythrocyte stagePlasmodium falciparum

Cited by 37 publications

References 39 publications

Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins

Safety and benefits of antenatal oral iron supplementation in low‐income countries: a review

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